The present invention provides for pharmaceutical compositions comprising carvedilol for treatment of cancer. More particularly the invention relates to the use of carvedilol for treatment of cancers of the colon, ovary, breast, prostate, pancreas, lung, melanoma, glioblastoma, oral cancer and leukemias. Although not bound to any theory, the anticancer activity of carvedilol appears to be attributed to the inhibition of Epidermal Growth Factor and Platelet derived growth factor dependent proliferation of cancer cells. Further, carvedilol exerts anticancer effect by inhibition of the Protein kinase C (PKC) activity and that of the cyclooxygenase 2 enzyme. The invention also relates to the anticancer activity of the optically pure isomers S(xe2x88x92) and R(+) of carvedilol and the use of carvedilol and its isomers in pharmaceutical compositions for the treatment of cancer.
Carvedilol is a nonselective xcex1-adrenergic blocking agent with xcex2-adrenoreceptor blocking activity. (xc2x1)-1-(carbazol-4-yloxy)-3-[(2-(o-methoxyphenoxy)ethyl]amino]-2-propanol, better known as xe2x80x98carvedilolxe2x80x99 has the structural formula shown in FIG. 1. It is a racemic mixture. Carvedilol is a white to off-white powder with a molecular weight of 406.5, represented by the molecular formula C24H26N2O4. Carvedilol is a racemic mixture in which the S(xe2x88x92) enantiomer exhibits nonselective xcex2-adrenoreceptor blocking activity and both R(+) and S(xe2x88x92) enantiomers at equal potency exhibit xcex1-adrenergic blocking activity. Carvedilol has no intrinsic sympathomimetic activity. 
Carvedilol is rapidly and extensively absorbed following oral administration due to a significant degree of first-pass metabolism. Following oral administration, the apparent mean terminal elimination half-life of carvedilol generally ranges from 7 to 10 hours. Carvedilol is extensively metabolized. Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation. The oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation. The metabolites of carvedilol are excreted primarily via the bile into the faeces. Demethylation and hydroxylation at the phenol ring produce three active metabolites with xcex2-receptor blocking activity. Based on preclinical studies, the 4xe2x80x2-hydroxyphenyl metabolite is approximately 13 times more potent than carvedilol for xcex2-blockade. Compared to carvedilol, the three active metabolites exhibit weak vasodilating activity. (12000 Mosby""s GenRx, the complete reference for Generic and Brand Drugs, Carvedilol (003267)).
Carvedilol is indicated for the treatment of mild or moderate heart failure of ischemic or cardiomyopathic origin, in conjunction with digitalis, diuretics, and ACE inhibitor, to reduce the progression of disease as evidenced by cardiovascular death, cardiovascular hospitalization, or the need to adjust other heart failure medications. Carvedilol may be used in patients unable to tolerate an ACE inhibitor. Carvedilol may be used in patients who are or are not receiving digitalis, hydralazine or nitrate therapy. Carvedilol is also indicated for the management of essential hypertension. It can be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics.
Carvedilol, is an antihypertensive drug with activity on xcex1-adrenoceptors as well as calcium channel activity. Use of carvedilol in compositions for treatment of congestive heart failure is disclosed in U.S. Pat. Nos. 4,503,067 and 5,902,82. U.S. Pat. No. 4,369,326 discloses carbazolylmethane compounds useful as pressure sensitive or heat recording material. Also carvedilol has been explored for treatment of sexual impotence (U.S. Pat. No. 5,399,581). U.S. Pat. No. 6,096,777 provides a new method for inhibiting the expression of Fas-mediated apoptosis using compounds which are dual non-selective xcex2-adrenoceptor and xcex11-adrenoceptor antagonists such as carvedilol.
Carvedilol is reported to be a neurohumoral antagonist with multiple actions. Essentially a nonselective adrenergic receptor blocking agent, it has diverse reported properties viz. antioxidant and radical scavenging properties. It inhibits Mitogen activated protein kinase, a key serine/threonine kinase and cell cycle progression in vascular smooth muscle cells. (Sung etal, Pharmacology and Experimental therapeutics, Vol 283, Issue 2, 910-917, 1997).
The cellular signaling routes connecting the GPCRs to the Ras/MAPK pathway have known to involve Tyrosine kinases, PI3 kinases and/or PKC (Gutkind et al., J. Biol Chem, 273,1839-1842, 1998). The ligand independent activation (transactivation) of receptor Tyrosine kinases viz. EGFR, as a key cellular event in the activation of MAPK by specific G protein coupled receptors is also reported (Daub etal, EMBO J. 16, 7032-7044, 1997, Daub etal, Nature,379, 557-560,1996). GPCR activation of Protein kinase C leading to EGFR transactivation and downstream MAPK activation, may be PKC mediated (Tsai etal, EMBO J, 16: 4597-4605, 1997), PKC prevented (Li X etal EMBO J, 17: 2574-2583, 1998), or PKC independent (Daub et al., EMBO J, 16, 7032-7044, 1997, Daub etal , Nature,379, 557-560,1996.
Tumor cells are well documented to produce autocrine and/or paracrine growth factors which can include platelet derived growth factor (PDGF), epidermal growth factor (EGF), transforming growth factor xe2x88x9d (TGFxe2x88x9d), colony stimulating growth factor 1(CSF-1), and fibroblast growth factor (FGF). Growth factors regulate cell growth by activating multiple intracellular signal transduction pathways after binding to high affinity Tyrosine kinase receptors to the cell surface.
Protein kinase C (PKC) is a family of closely related lipid dependent and diacylglycerol activated isoenzymes, with an important role in mitogenesis and tumor promotion. Sustained activation of PKC activity in vivo plays a critical role in regulation of proliferation and tumorigenesis (Blobe et al., Regulation of Protein kinase C and role in Cancer Biology, Cancer Metastasis Rev. 13 (3-4): 411-431, Dec. 13, 1994).
Acquired resistance to chemotherapy is a major problem during cancer treatment. One mechanism for drug resistance is overexpression of the MDR1 (multidrug resistance) gene encoding for the transmembrane efflux pump, P-glycoprotein (P-gp). Carvedilol influences doxorubicin (Dox) cytotoxicity and P-gp activity in a P-gp-expressing cell line compared to a non-expressing subline. Carvedilol reduced P-gp activity approximately twice as effectively as verapamil at an equimolar concentration. This suggests that carvedilol has the clinical potential to reverse tumour MDR involving the efflux protein P-gp.
The invention involves methods for treating various types of cancer in patients using carvedilol or its optically pure isomers.
The present invention provides pharmaceutical compositions containing carvedilol or its optically pure isomers useful in the treatment of cancer. In particular, the invention provides novel method for treating, inhibiting and/or preventing tumor growth or cancer growth.
Based on the multiple actions of Carvedilol, a study was undertaken to investigate the use of carvedilol for treatment of cancer. It was found by the inventors that carvedilol caused cytotoxicity on different human tumor cell lines depending on the dosage and cell-line used. Carvedilol was separated into its optically pure isomers S(xe2x88x92) and R(+) to determine their use as anticancer agents. The underlying cellular mechanism(s) that may be determining of the observed anticancer effects were investigated.
The effect(s) of Carvedilol on Growth factor dependent mitogenic signaling in cancer cells was investigated. In the context of documented cross talk between the signaling intermediates of G protein coupled receptors and the Tyrosine kinase receptors, the effects of Carvedilol on PKC and PI3 kinase activity was investigated. The effect of Carvedilol on the activity of Cyclooxygenase 2 enzyme and its regulation by selected upstream mediators of these two pathways was also investigated.